Genomic predictors of good outcome, recurrence or progression in High grade T1 non-muscle invasive bladder cancer.

High-grade T1 (HGT1) bladder cancer (BC) is the highest risk subtype of non-muscle-invasive BC with unpredictable outcome and poorly understood risk factors. Here we examined the association of somatic mutation profiles with non-recurrent disease (GO:good outcome), recurrence (R), or progression (PD) in a cohort of HGT1 patients. Exome sequencing was performed on 62 HGT1 and 15 matched normal tissue samples. Both tumor only (TO) and paired analysis was performed, focusing on 95 genes known to be mutated in BC. Somatic mutations, copy number alterations, mutation load, and mutation signatures were studied. Thirty-three GO, 10 R, 18 PD, and 1 unknown outcome patients were analyzed. Mutation burden (TMB) was similar to muscle-invasive disease and was highest in GO, intermediate in PD, and lowest in R patients (p=0.017). DNA damage response gene mutations were associated with higher TMB (p<0.0001) and GO (p=0.003). ERCC2 and BRCA2 mutations were associated with GO. TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequent in PD. Focal copy number gain in CCNE1 and CDKN2A deletion were enriched in PD or R (p=0.047; p=0.06). APOBEC (46%) and COSMIC5 (34%) signatures were most frequent. APOBEC-A and ERCC2 mutant tumors (COSMIC5) were associated with GO (p=0.047; p=0.0002). pT1b microstaging was associated with a genomic cluster (p=0.05) with focal amplifications of E2F3/SOX4, PVRL4, CCNE1, and TP53 mutations. Findings were validated using external public datasets. These findings require confirmation but suggest that management of HGT1 bladder cancer may be improved via molecular characterization to predict outcome.